Jack Bruno (Dwayne Johnson) is a cab driver in Las Vegas. One of his passengers is Dr. Alex Friedman (Carla Gugino), a failed scientist who is giving speeches about legitimate scientific theories of UFOs and outer space.

The next day, Bruno notices two children, Sara (AnnaSophia Robb) and Seth (Alexander Ludwig) sitting in the back seat of his cab. They tell him they need to go to a certain destination and are willing to pay all they have ($15,000, they removed from an ATM) to get there. They lead him to a house in the middle of nowhere. Meanwhile, Major Henry Burke (Ciaran Hinds) is searching for information on the two aliens that landed some days earlier.

When they arrive at the house, Bruno follows them out of concern and curiosity. There, the kids retrieve their objective, a device contained within alien flora.

When leaving, they are attacked by a "Siphon", a creature built to destroy a certain target. The Siphon pursues them, until its spaceship crashes into a train, the Diesel Locomotive is destroyed by an explosion in the railroad tunnel, and the creature is wounded. The trio eventually find themselves in a small town. The children explain to Bruno that they are aliens from a distant planet, who are sent to Earth by their parents because the government of their dying planet intends to attack and invade Earth so that their kind may live on there. They also explain that the object they obtained at the house contains the results of an experiment which their parents set up. The research from this experiment will save their planet without having to attack and invade Earth. However their planet's military prefer the idea of invading Earth and sent the Siphon assassin to stop them. They are next pursued by government agencies trying to retrieve the children for experiments.

They are joined by Dr. Friedman at the UFO Expo. With help of one of Dr. Friedman's friends, the kids discover that their crashed spaceship has been relocated to a government base at Witch Mountain. The group, now including Dr. Friedman, after evading the pursuing government agents, eventually arrive at Witch Mountain. There, the children are captured, along with Bruno and Friedman. Nevertheless, the two humans escape and come to rescue the kids. The Siphon causes a distraction by attacking the base, allowing the humans to free the children and reach their ship. They launch the ship, escape through the mountain's tunnels and defeat the Siphon who boarded the ship. Once safe, the kids drop the humans off, and during a tearful goodbye, give Bruno and Dr. Friedman a device that will allow the kids to always find them. Sara also gives Bruno the ability to read minds. The movie ends with the spaceship taking off and returning to their planet.

During the end credits, Bruno and Dr. Friedman (now a couple) are speaking at a UFO convention about their new successful book called "Race to Witch Mountain". As they are about to leave, the device the kids gave Bruno activates, indicating that they may be returning.